Platform Research for Innovative Medicines in NF2-SWN (PRIME-NF2)

Phase 2Not Yet RecruitingNCT07713745

Beijing Tiantan Hospital200 enrolled

Overview

This is an adaptive platform-basket trial that aims to evaluate the safety and efficacy of multiple novel agents and combination therapies in patients with NF2-related schwannomatosis (NF2-SWN). The study employs a basket design to assess treatment responses across four tumor types commonly associated with NF2-SWN: vestibular schwannomas, non-vestibular schwannomas, meningiomas, and ependymomas. A shared natural history observational cohort, receiving routine clinical follow-up without investigational treatment, serves as a common control for all substudies. The adaptive platform enables the dynamic addition or closure of substudies based on interim analyses, thereby optimizing trial efficiency. Eligible patients who meet the master protocol criteria and satisfy substudy-specific safety requirements will be assigned to receive the corresponding intervention. Currently open substudies include: * Substudy A: Selumetinib * Substudy B: Luvometinib plus Serplulimab

This is an investigator-initiated, prospective, multicenter, adaptive platform-basket clinical trial designed to evaluate the safety and efficacy of multiple therapies in patients with NF2-related schwannomatosis (NF2-SWN). The study includes four tumor baskets: vestibular schwannoma, meningioma, non-vestibular schwannoma, and ependymoma. MASTER STUDY All patients with a confirmed diagnosis of NF2-SWN who provide written informed consent will be enrolled in the master study and enter the natural history observational cohort. Patients who meet eligibility criteria for one or more active substudies may be assigned to a corresponding treatment arm. When multiple treatment arms are open, allocation will follow a predefined randomization scheme. When only one treatment arm is available, eligible patients may be enrolled directly into that substudy. Patients not eligible for any active intervention will remain in the master study cohort for standardized follow-up. Patients who experience progression of the target tumor during substudy treatment may be considered for enrollment into another active treatment arm if eligibility criteria are met. Patients who are not eligible for any active substudy will return to the master study observational cohort. Data collected during follow-up may serve as shared control data across the platform. Patients in the observational cohort will undergo standardized follow-up assessments every 12 months until study completion or voluntary withdrawal. Patients receiving treatment within a substudy will undergo efficacy and safety assessments approximately every 3 months according to the corresponding substudy protocol. The master study plans to enroll at least 200 patients with NF2-SWN, with enrollment continuing over time as eligible patients are identified across participating centers. SUBSTUDY 1: Selumetinib * Selumetinib is a selective MEK1/2 inhibitor approved for the treatment of NF1-associated plexiform neurofibromas. It inhibits tumor growth through blockade of the RAS/RAF/MEK/ERK signaling pathway. * This substudy plans to enroll 20 patients, prioritizing those with vestibular schwannoma as the target tumor. Detailed eligibility criteria are provided in the substudy protocol. SUBSTUDY 2: Luvometinib + Serplulimab * Luvometinib is a selective oral MEK1/2 inhibitor. Serplulimab is a humanized anti-PD-1 monoclonal antibody that blocks PD-1 signaling and restores T-cell-mediated antitumor immune activity by preventing interaction with PD-L1 and PD-L2. * This substudy plans to enroll approximately 30 adult patients, prioritizing those with vestibular schwannoma or meningioma as the target tumor. Detailed inclusion and exclusion criteria are described in the substudy protocol. Each substudy protocol will be incorporated into the master protocol as an appendix. Addition of new substudies requires review and approval by the Data and Safety Monitoring Board (DSMB). Efficacy will be evaluated using tumor-specific endpoints. For vestibular schwannoma, the primary endpoint is Hearing Response Rate (HRR). For meningioma, non-vestibular schwannoma, and ependymoma, the primary endpoint is radiographic Objective Response Rate (ORR). All efficacy endpoints will undergo blinded central review by an Independent Review Committee (IRC). The platform is expected to remain active for 5-10 years, or until all active substudies are completed and no additional treatment arms are planned.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Eligibility Specific For MASTER STUDY Inclusion Criteria: Subjects must satisfy all of the following criteria to be enrolled into the main study natural history observation cohort: (1) Must meet the 2022 International Consensus Criteria for NF2-SWN, defined by having at least one of the following: 1. Bilateral vestibular schwannomas (VS) 2. An identical NF2 pathogenic variant in at least 2 anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma). (Note: if the variant allele fraction (VAF) in unaffected tissues such as blood is clearly \<50%, the diagnosis is mosaic NF2-related schwannomatosis) 3. Either 2 major or 1 major and 2 minor criteria as described in the following: Major criteria: * Unilateral VS * First-degree relative other than sibling with NF2-related schwannomatosis * 2 or more meningiomas (Note: single meningioma qualifies as minor criteria). * NF2 pathogenic variant in an unaffected tissue such as blood (Note: if the VAF is clearly \<50%, the diagnosis is mosaic NF2-related schwannomatosis) Minor criteria: Can count \>1 of a type (eg, 2 distinct schwannomas would count as 2 minor criteria) * Ependymoma, meningioma (Note: multiple meningiomas qualify as a major criteria), schwannoma (Note: if the major criterion is unilateral VS, at least 1 schwannoma must be dermal in location) Can count only once (eg, bilateral cortical cataracts count as a single minor criterion) * Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person aged \<40 years, meningioma (2) Presence of at least one evaluable lesion: Vestibular schwannoma, meningioma, or non-vestibular schwannoma: clearly identifiable lesion on contrast-enhanced T1-weighted MRI; Ependymoma: clearly identifiable lesion on contrast-enhanced T1-weighted or T2/FLAIR sequences; (3) Expected ability to complete at least 12 months of follow-up assessments; (4) Ability to understand and voluntarily sign a written informed consent form, or a legally authorized guardian signs the informed consent form together ; (5) Sub-study-specific criteria (for intervention arms only): If the subject intends to enter an interventional sub-study, in addition to meeting the above main study criteria, the subject must also satisfy the specific inclusion criteria specified in that sub-study protocol (e.g., organ function, prior treatment restrictions, washout periods, etc.), as determined by the drug characteristics. Exclusion Criteria: Subjects meeting any of the following criteria will not be permitted to enter the main study: 1. Coexisting other genetic syndromes that may cause multiple intracranial tumors (e.g., SMARCB1/LZTR1-related schwannomatosis, Cowden syndrome); 2. Expected survival \<12 months; 3. Presence of severe psychiatric disorders or cognitive impairment that precludes cooperation with imaging or hearing assessments; 4. Extreme social or geographic factors that, in the investigator's judgment, may impede follow-up for more than 12 months; 5. Sub-study-specific exclusion criteria (for intervention arms only): If the subject intends to enter an interventional sub-study, the subject must also satisfy the specific exclusion criteria specified in that sub-study protocol (e.g., specific organ dysfunction, active infection, pregnancy, etc.).

Outcomes

Primary Outcomes

Tumor-Type-Specific Response Rate in NF2-SWN Tumors

Vestibular schwannoma: HRR is defined as WRS improvement exceeding the 95% critical difference from baseline; if baseline WRS is \<20%, HRR is defined as a PTA decrease of at least 10 dB. Meningioma or non-vestibular schwannoma: ORR is defined as at least a 20% reduction in target tumor volume from baseline. Ependymoma: ORR is defined as at least a 30% reduction in maximum diameter from baseline according to RECIST v1.1.

Time frame: 12 months

Secondary Outcomes

Incidence of Adverse Events in Interventional Substudies

Percentage of participants receiving active treatment who experience at least one adverse event. Adverse events will be coded and graded according to NCI CTCAE v5.0.

Time frame: From first dose through 30 days after last dose (or as specified by individual substudy protocols)

Maximum Severity Grade of Adverse Events in Interventional Substudies

Maximum NCI CTCAE v5.0 grade of adverse events experienced by each participant during the reporting period.

Time frame: 12 months

Incidence of Serious Adverse Events in Interventional Substudies

Percentage of participants receiving active treatment who experience at least one serious adverse event.

Time frame: From first dose through 30 days after last dose.

Incidence of Dose Modifications Due to Adverse Events

Percentage of participants receiving active treatment who require at least one dose modification due to an adverse event.

Time frame: From first dose through 30 days after last dose.

Incidence of Treatment Interruptions Due to Adverse Events

Percentage of participants receiving active treatment who require at least one treatment interruption due to an adverse event.

Time frame: From first dose through 30 days after last dose.

Incidence of Treatment Discontinuations Due to Adverse Events

Percentage of participants receiving active treatment who discontinue treatment due to an adverse event.

Time frame: From first dose through 30 days after last dose.

Platform Research for Innovative Medicines in NF2-SWN (PRIME-NF2)

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes